Aging, immunosenescence and glioblastoma

项目总结 高龄是成人诊断为野生型胶质母细胞瘤的主要因素 异柠檬酸脱氢酶；占所有GBM诊断的90%，是最常见的侵袭性原发疾病 中枢神经系统(CNS)脑瘤。成人GBM与中位总生存期(OS)相关 15个月，随着年龄的增长，预后明显下降。由于护理治疗的标准 包括最大限度的手术切除、放疗和替莫唑胺(TMZ)化疗不可避免地导致 为了达到100%的死亡率，免疫疗法被认为是未来治疗GBM患者的一种潜在方法， 基于它在治疗其他侵袭性癌症患者方面的成功。然而，与不断增长的名单形成对比的是 对于对抗PD-1单抗和/或抗CTLA-4单抗治疗有利的终末期恶性肿瘤， 到目前为止，被诊断患有基底膜并接受免疫治疗的患者并未表现出好转。 到目前为止所有III期临床试验的存活率。因此，我的K02应用程序的目标是定义 随着年龄的增长，抑制抗GBM免疫反应的免疫抑制因子增加， 以及了解衰老增加的免疫抑制吲哚胺2，3双加氧酶1(IDO1)非 典型地降低对免疫治疗的反应。我的团队之前的工作发现，高级 衰老增加了正常人类和小鼠大脑中免疫抑制基因IDO1的表达。我们也 研究表明，放射治疗(RT)联合抗PD-1单抗和IDO1的免疫治疗 酶抑制剂，导致6-12周龄免疫活性小鼠长期(≥150天)存活受益 颅内基底膜。令人惊讶的是，这种治疗在提高老年人存活率方面的有效性明显降低。 受试者在植入完全相同的肿瘤细胞时。我的工作假设是，超前衰老会增加 中枢神经系统中的免疫抑制限制了负责预防的免疫监测机制 GBM细胞生长并抑制免疫系统对免疫治疗的反应性。受保护的人 K02支持期间的时间将允许进行针对老化的全面培训，并与专家进行高级别互动 具有探索衰老、癌症和/或癌症之间相互作用的广泛经验的科学家委员会 免疫反应，并将为我提供必要的时间来开发具有竞争力的R01应用程序 支持一个未来的研究计划，重点是在GBM的背景下老化；一种仍然无法治愈的疾病。

PROJECT SUMMARY Advanced aging is the primary factor associated with an adult diagnosis of glioblastoma (GBM) with wild-type isocitrate dehydrogenase; constituting 90% of all GBM diagnoses and the most commonly aggressive primary brain tumor of the central nervous system (CNS). Adult GBM is associated with a median overall survival (OS) of 15 months and the prognosis significantly decreases with progressive aging. Since standard of care treatment including maximal surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ) inevitably leads to a 100% mortality rate, immunotherapy has been proposed as a potential future approach for GBM patients, based on its success in treating patients with other aggressive cancers. However, in contrast to the growing list of end-stage malignancies that respond beneficially to anti-PD-1 mAb and/or anti-CTLA-4 mAb treatment, patients diagnosed with GBM and treated with immunotherapy have thus far failed to demonstrate an improved survival among all phase III clinical trials to-date. The goal of my K02 application is therefore to define the advanced aging-dependent increase of immunosuppressive factors that inhibit the anti-GBM immune response, as well as to understand how aging-increased immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO1) non- canonically decreases the response to immunotherapy. Previous work from my group discovered that, advanced aging increases immunosuppressive IDO1 gene expression in the normal human and mouse brain. We also showed that, immunotherapeutic treatment combining radiotherapy (RT) with anti-PD-1 mAb and an IDO1 enzyme inhibitor, leads to a long-term (≥150 days) survival benefit in 6-12 week old immunocompetent mice with intracranial GBM. Strikingly, the treatment was made significantly less effective at improving survival in older subjects when engrafted the exact same tumor cells. My working hypothesis is that, advanced aging increases immunosuppression in the CNS that limits immunosurveillance mechanisms responsible for preventing GBM cell outgrowth and suppressing immune system responsiveness to immunotherapy. The protected time during K02 support will allow for comprehensive aging-specific training, high-level interactions with an expert committee of scientists that have broad experience exploring the interactions between aging, cancer, and/or the immune response, and will provide me with the necessary time to develop competitive R01 applications to support a future program of research focused on aging in the setting of GBM; a disease that remains incurable.